Abstract

The broad aim of this research is to establish the molecular basis of skeletal and cardiac muscle assembly and function in the normal tissue and in heart failure. The major present goals are (1) to use molecular genetics to study the length dependency of cardiac muscle (Starling's law of the heart) by defining the amino acid residues responsible for the length sensing mechanism. Specific manipulations of the structure of TnC will be correlated with alterations in the cardiac and skeletal length-tension curves. (2) We propose to investigate the basis of cooperativity in the Ca2+-switching processes of the thin filaments in cardiac muscle. Also, by examining the interactions of force modifying compounds, such as TFP as well as cardiotonic agents, with the Ca-binding proteins and their genetic variants, we will examine whether the hydrophobic residues of TnC participate in setting the cooperativity level in the Ca-force relations in muscle. In addition we will study the specific role of the central helix in TnC and calmodulin in the switching mechanisms. In particular, we propose to determine whether the central linker between the N- and C-terminal lobes is essential to function. Further, by combining the mutation studies with computer simulations, we will examine whether the bending of the central helix that could cause compaction of the molecule, is essential for the molecular dynamics related to ligand binding, and also whether the highly conserved arginine residues are implicated in this function. (3) We also propose to characterize the properties of cofactor-B. Cofactor-B, discovered in this lab, is a protein essential for reconstitution of extracted fibers. Our goals are to purify, clone, mutate, determine isoformic diversity, and study the expression of cofactor-B in normal tissue as well as during the development of cardiomyopathy of the Syrian hamster. A major hypothesis is suggested that cofactor-B controls the link between the weak and strong cross-bridge states.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR033736-09
Application #
2078939
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1992-09-18
Project End
1996-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
9
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461

  Publications

Akella, A B; Su, H; Sonnenblick, E H et al. (1997) The cardiac troponin C isoform and the length dependence of Ca2+ sensitivity of tension in myocardium. J Mol Cell Cardiol 29:381-9
Ding, X L; Akella, A B; Sonnenblick, E H et al. (1996) Molecular basis of depression of Ca2+ sensitivity of tension by acid pH in cardiac muscles of the mouse and the rat. J Card Fail 2:319-26
Akella, A B; Sonnenblick, E H; Gulati, J (1996) Alterations in myocardial contractile proteins in diabetes mellitus. Coron Artery Dis 7:124-32
Ding, X L; Akella, A B; Gulati, J (1995) Contributions of troponin I and troponin C to the acidic pH-induced depression of contractile Ca2+ sensitivity in cardiotrabeculae. Biochemistry 34:2309-16
Gulati, J; Akella, A B; Su, H et al. (1995) Functional role of arginine-11 in the N-terminal helix of skeletal troponin C: combined mutagenesis and molecular dynamics investigation. Biochemistry 34:7348-55
Rao, V G; Akella, A B; Su, H et al. (1995) Molecular mobility of the Ca(2+)-deficient EF-hand of cardiac troponin C as revealed by fluorescence polarization of genetically inserted tryptophan. Biochemistry 34:562-8
Akella, A B; Ding, X L; Cheng, R et al. (1995) Diminished Ca2+ sensitivity of skinned cardiac muscle contractility coincident with troponin T-band shifts in the diabetic rat. Circ Res 76:600-6
Ding, X L; Akella, A B; Su, H et al. (1994) The role of glycine (residue 89) in the central helix of EF-hand protein troponin-C exposed following amino-terminal alpha-helix deletion. Protein Sci 3:2089-96
Keleti, D; Rao, V G; Su, H et al. (1994) Disparate contributions of Tyr10 and Tyr109 to fluorescence intensity of rabbit skeletal muscle troponin C identified using a genetically engineered mutant. FEBS Lett 354:135-9
Gulati, J; Rao, V G (1994) The cardiac Ca(2+)-deficient EF-hand governs the phenotype of the cardiac-skeletal TnC-chimera in solution by Sr(2+)-induced tryptophan fluorescence emission. Biochemistry 33:9052-6

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